Updated NCCN Guidelines for Neuroendocrine Tumors and Carcinoid Syndrome Features New Therapies

Orlando, FL—Somatostatin analogs have multiple roles in the treatment of neuroendocrine tumors (NETs), including the management of symptoms of hormone hypersecretion and, more recently, slowing tumor progression.

The latest guideline from the National Comprehensive Cancer Network (NCCN), version 1.2017, recommends a somatostatin analog as initial treatment of metastatic carcinoid syndrome, because these drugs are well-tolerated and have been shown to slow tumor progression.

Key components of the guideline were presented by Matthew H. Kulke, MD, MMSc, Director, Program in Neuroendocrine and Carcinoid Tumors, Dana-Farber/Brigham and Women’s Cancer Center, Boston, at the 2017 NCCN annual conference.

NETs constitute a broad spectrum of malignancies and are categorized as grade 1 (low), grade 2 (intermediate), or grade 3 (high) based on their mitotic count and Ki-67 index. Grade 3 tumors are poorly differentiated with a mitotic count >20 and a Ki-67 index >20%.

NETs are also differentiated by their site of origin—pancreatic, endocrine, or carcinoid tumors. Some 60% to 70% of pancreatic NETs are nonfunctioning and 30% to 40% are associated with symptoms of hormone hypersecretion, said Dr Kulke.

Carcinoid tumors are subcategorized by their presumed derivation in the gut—foregut, midgut, or hindgut.

Preventing Disease Progression

Patients with metastatic NETs “often do well for several years, but metastatic disease in most cases remains fatal, so it really is important to identify effective treatments for these patients to try to prevent progression and hopefully improve overall survival,” said Dr Kulke.

NETs frequently express somatostat­in receptors, which has led to the development of somatostatin receptor-based imaging techniques. Detection of local and metastatic NETs historically has been accomplished with octreotide scans, but a newer method that has much higher resolution is 68Ga-Dotatate positron emission tomography (PET)/computed tomography (CT), he said. The NCCN guideline now includes 68Ga-Dotatate PET/CT as another imaging option for evaluation of advanced NETs.

Somatostatin analogs are a mainstay in the management of hormone hypersecretion. One of the most common syndromes caused by excretion of serotonin and other neuropeptides into the circulation is carcinoid syndrome. Patients with carcinoid syndrome generally have episodic flushing and sometimes profound diarrhea, and eventually right-sided valvular heart disease develops.

In addition to symptomatic treatment, somatostatin analogs were shown in 2 randomized clinical trials, one involving octreotide and the other lanreotide, to slow tumor progression.

“Based on these 2 studies, the guideline for management of carcinoid tumors suggests that at the outset, because these drugs are so well-tolerated, treatment with octreotide or lanreotide be considered in patients as the initial treatment for slowing tumor progression,” said Dr Kulke.

Based on the CLARINET study, treatment with somatostatin analogs is now recommended for patients with advanced pancreatic NETs to slow disease progression.

“These patients can live for many years, and over time the efficacy of somatostatin analogs wears off,” said Dr Kulke.

A new option is the tryptophan hydroxylase inhibitor telotristat ethyl, which was approved by the FDA in February 2017 for patients with carcinoid syndrome diarrhea despite treatment with a somatostatin. In the randomized phase 3 clinical trial, telotristat ethyl was associated with a significant reduction in daily bowel movement frequency compared with placebo in patients with carcinoid syndrome whose diarrhea continued to be a serious burden despite treatment with a somatostatin analog.

Data suggest that alkylating agents are effective in pancreatic NETs. Response rates to streptozocin-based therapy are 30% to 40%. Streptozocin is toxic and difficult to administer, however, which has led to interest in temozolomide. In prospective studies of temozolomide alone or in combination, the response rates were in the range of 33% to 64%. Although temozolomide is often used for pancreatic NETs, “the fact is we really don’t know how best to use it, what regimen to use, and whether it’s best alone or in combination,” Dr Kulke said.

Molecularly targeted therapies have been particularly exciting in the realm of advanced pancreatic NETs, said Dr Kulke. Sunitinib and evero­limus improved progression-free survival (PFS) compared with placebo in patients with pancreatic NETs, leading to their subsequent FDA approval in this setting. The NCCN guideline for patients with advanced pancreatic NETs lists everoli­mus, sunitinib, and cytotoxic chemotherapy as second-line options after first-line treatment with a somatostatin analog.

Carcinoid tumors respond to cytotoxic agents in a different way from pancreatic NETs, and cytotoxic agents are “very rarely” used in patients with advanced carcinoid syndrome for this reason, he said. In the RADIANT study, everolimus treatment in patients with well-differentiated advanced progressive nonfunctional NET of lung or gastrointestinal origin improved PFS by 7 months compared with placebo, leading to its subsequent FDA approval and inclusion in the NCCN guideline for the treatment of advanced carcinoid syndrome with disease progression despite somatostatin analog therapy.

What’s in the Near Future?

“One of the most exciting developments in this field has been peptide receptor radionuclide therapy” (PRRT), Dr Kulke said. In the NETTER-1 phase 3 clinical trial, the PRRT known as 177Lu-Dotatate demonstrated improvement in PFS versus high-dose octreotide (median PFS not yet reached vs 8.4 months) in patients with midgut carcinoid.

“This drug at present is being considered by the FDA, and we look forward eagerly as to what happens over the next several months as it gets reviewed,” Dr Kulke said.

Inhibiting the VEGF pathway with tyrosine kinase inhibitors is also being investigated in pancreatic NETs and carcinoid syndrome. A phase 2 clinical trial of cabozantinib demonstrated responses in a majority of patients in both settings, with 90% partial response and 78% stable disease as best response. A phase 3 clinical trial of cabozantinib is being considered in patients with advanced pancreatic NETs or advanced carcinoid syndrome.